Prior Art
Many disease states encountered in humans and animals are difficult to correct by drug administration, regardless of whether the drug is delivered orally or parenterally. This problem is often due to the fact that the drug cannot reach the appropriate site of action or that it exhibits unacceptable side effects.
Bipolar lipid vesicles are a known and relatively new biochemical approach being intensely studied as possible carriers of drugs, hormones, nutrients and pharmacological agents.
Bipolar lipid vesicles are synthesized by sonicating ampholiphilic long-chain lipid compounds such as distearoyl lecithin. The sonication process produces high frequency sound waves and initiates a reaction sequence which causes the lipid chains to fragment. The dispersed lipid then assumes a spherical shape which has a greater thermodynamic stability than individual fragments. During the formation of the spherical vesicle, some of the pharmacological agent is captured and internalized within the vesicle core volume.
Some vesicles are intended to circulate in the blood stream and designed to slowly release their core volume contents in order to provide a sustained release of drug over an extended period of time.
Other vesicles are supplied with target molecules which are recognized by selected tissues and cell types. In this way, the hormone insulin, for example, may be delivered to the liver. See Geho, U.S. Pat. No. 4,377,567, issued on Mar. 22, 1983.
One persistent problem associated with vesicle technology has been very short vesicle shelf life, which necessitates manufacturing vesicles very soon before their use and in relatively small quantities. This type of special manufacture is prohibitively expensive. Some preparations have reported shelf lives on the order of several months, but most experience has indicated that vesicles exhibit a shelf life that is measured in weeks. A short vesicle shelf life inhibits wide-scale manufacture and distribution, thereby limiting the use of vesicles to special situations and small-scale research applications.
Vesicle instability has two important features: first, vesicles lose their structural integrity with time; and secondly, the structural lesions result in the leaking of the core volume content to the external media. Once the contents of the vesicle core volume are leaked to the external media, they can no longer be targeted.
After manufacture, vesicles are suspended in a buffer solution that has the appropriate physiological pH and ionic strength to effectively ionize the charged functional groups. Vesicles may be negatively or positively charged depending upon the type of charged ampholiphilic materials incorporated into the vesicle membrane. Examples of negatively and positively charged lipids are dicetyl-phosphate and stearylamine. As a consequence of membrane incorporation of charge groups, an ion atmosphere is developed which results in a charge-charge repulsion between neighboring vesicles that contribute to their short term stability. However, after a period of time ranging from a few weeks to several months, the charge-charge repulsion becomes neutralized, and the vesicles begin to aggregate and eventually fuse. From a morphological point-of-view, the vesicles are undergoing transformation from a colloid dispersion to a coarse suspension.
When fusion occurs, the lipid membrane structures deteriorate rapidly, and the vesicles lose their core volume constituents. The deteriorated membranes coalesce and aggregate on the bottom of the storage vial. As a result of this sequence of events, the vesicle preparation is unsuitable for further use.